Lecture 39: OBESITY Flashcards
How does the WHO classify obesity?
By BMI
What is the formula for BMI?
weight(kg)/height(m) ^2
What is a BMI >30?
Obese
What is a BMI 25 to 30?
Overweight
What is a BMI 20 to 25?
healthy weight
What is a BMI <20?
Underweight
What increases with increasing BMI?
Risk of type 2 diabetes and CHD
What may abnormal TAG storage in muscle and liver contribute to?
Insulin resistance
How do 90% of people return to original weight?
By diet and exercise meaning that they lose fat
What is metabolic rate made up of?
Adaptive thermogenesis (smallest component), physical activity and obligatory energy expenditure (largest component)
What is adaptive thermogenesis?
Variable, regulated by the brain
What does adaptive thermogenesis respond to?
Temperature and diet
Where does adaptive thermogenesis occur?
In brown adipocyte mitochondria, skeletal muscle and other sites
What is physical activity?
Variable
What is obligatory energy expenditure required for?
Performance of cellular and organ function
What happens when respiration is uncoupled to oxidative phosphorylation?
Heat is produced rather than ATP as the ETC goes faster to try and re-establish the gradient
Where were uncoupling proteins originally found?
In brown fat
Where are uncoupling proteins present?
In the inner mitochondrial membrane
What are uncoupling proteins?
Regulated proton channels in the membrane (“holes”) which remove the proton gradient
What is an example of an uncoupling protein?
2,4 - dinitrophenol
What do uncoupling proteins do?
Uncouple ATP synthesis from fatty acid oxidation which causes the electrochemical potential gradient to dissipate releasing heat which therefore increases metabolic rate and burns excess fuels
When are proton channels open and closed?
Open in cold and closed in warm
How are UCP’s regulated?
By the sympathetic nervous system (SNS)/noradrenaline
What is the main neurotransmitter of the SNS?
noradrenaline
What is brown fat?
Special thermogenic tissue
Where is brown fat found?
In hibernating animals, babies and less in adults
What does brown fat do?
Keeps hibernating animals and babies warm
What does brown fat have?
Many mitochondria and fat droplets
What is the metabolic adaptation to cold in penguins?
avian uncoupling protein (avUCP)
Where is avUCP highly expressed?
In the mitochondria of pectoral muscles
What does avUCP do?
Oxidises fatty acids to generate heat
What has recently been discovered?
Uncoupling proteins (UCP2, UCP3) in white adipose tissue and in muscle of humans as well as other animals
What may UCP2 and UCP3 do?
Act to raise the metabolic rate and release heat to burn off some excess energy and prevent obesity
What are some strategies to combat obesity (involving BAT)?
stimulate existing BAT, switch on brown fat differentiation and growth, transplantation of engineered BAT
What may be involved in switching on brown fat differentiation and growth?
PRDM16 promoter inserted into developing white adipose tissue to promote brown adipose tissue growth
What does the in vivo approach: pharmaceuticals, biologics and natural components to BAT involve?
increase BAT differentiation from progenitor cells, activated BAT - mediated thermogenesis, promote muscle thermogenic function and increase general mitochondrial uncoupling
What is involved in the ex vivo: cell based therapy approach?
1: isolate progenitor
2: induce in vitro with agents promoting BAT differentiation or genes specifying BAT differentiation
3: transplant back to donor to generate functional BAT
What is the component of obesity from genes?
30-80%
What is also involved in obesity other than genetics?
Environmental and lifestyle factors
What are the genetic defects in rodents?
Obese mouse ob/ob
diabetic obese mouse db/db
fatty rat fa/fa
What does the obese gene code for?
leptin - a 16kDa protein
What does the mutant obese mouse (ob/ob) do?
Not produce leptin
What is leptin?
A peptide hormone secreted from fat cells
What does leptin do?
Signals the brain to decrease food intake, increase energy expenditure and therefore maintains normal animal in energy balance
Where is the leptin receptor found?
In the hypothalamus of the brain and several other tissues
Where is the leptin receptor absent?
In the obese diabetic (db/db) and the fatty rat (fa/fa)
What are some obese humans found to have?
mutant leptin or leptin receptor
What do most obese humans appear to be?
Resistant to the leptin signal
What did the severely obese child have?
No serum leptin, homozygous for frameshift mutation in the leptin gene
What treatment was the severely obese child given?
Recombinant leptin therapy for a year
What did the treatment do for the severely obese child?
Decreased food intake and 16kg weight loss in 1 year due to fat oss
What are some other defects in the cell signalling pathway of leptin which cause obesity?
MC4R = 4-6% of severe human obesity POMC= bariatric surgery may be required
What are factors influencing the development of obesity?
genes, monogenic syndromes, susceptibility genes, exercise, food intake, culture and environmental factors
What are potential molecular targets for anti-obesity drugs?
Food breakdown, satiety signals, mitochondria and brown fat as well as microbiome
What can be targeted for food breakdown?
Pancreatic lipase may be blocked so less fat is absorbed (xenical)
What can be adjusted in satiety signals?
Increase leptin levels (leptin receptor), gut satiety factors -clinical trials underwya
What can be targeted in mitochondria and brown fat?
Uncouple oxidative phosphorylation from electron transport and up regulate uncoupling proteins with drugs increasing functional BAT (future?)
what does leptin stimulate?
Sympathetic neurone activation > lipolysis
What is adipose tissue?
An endocrine organ which secretes regulatory molecules which is why having too much can disrupt the pathway
